The specific aim of this proposal is to test the hypothesis that adenosine is the primary mediator of coronary autoregulation. If the hypothesis is correct then destruction of interstitial adenosine should result in abolition or at least attenuation of the autoregulatory capability of the coronary circulation. To test this hypothesis adenosine deaminase (ADA) will be used to destroy interstitial adenosine in 4 groups of closed chest conscious swine. In Group I, ADA will be infused directly into the left anterior descending (LAD) coronary artery under resting conditions. The response in terms of regional myocardial blood flow (RMBF-Microsphere technique), mechanical function (ultra-sonic length sensors), oxygen, lactate and adenosine metabolism will be measured. In Group Ii myocardial oxygen demand will be augmented by simultaneous intravenous infusion of norepinephrine and atrial pacing. Experimental parameters (i.e.; RMBF, mechanical function, metabolism of oxygen, lactate, adenosine) will be measured and compared in the presence and absense of simultaneous ADA infusion into the animal's LAD. In Group III an artificial coronary artery stenosis which reduces vessel diameter by 82% will be placed in the animal's LAD. Measurements of experimental parameters will be made prior to, during and following ADA infusion directly into the LAD bed distal to the stenosis to determine if adenosine destruction by ADA causes a deterioration in RMBF, mechanical function, and/or metabolic evidence of ischemia. Finally, in Group IV animals also will be instrumented with a severe LAD stenosis. We have previously shown that epicardial blood flow distal to the stenosis increases significantly in this model in response to atrial pacing. To evaluate the role of adenosine in mediating this response we will measure RMBF, mechanical function and metabolic parameters when atrial pacing is performed in the presence and absense of ADA infused directly into the LAD bed distal to the stenosis. The combined series of experiments will serve as a test of the hypothesis that adenosine is the primary mediator of coronary autoregulation under a variety of conditions. These experiments are part of a long range program to study mechanism(s) of autoregulation of coronary blood flow particularly in the setting of a severe coronary artery stenosis. Collaboration between clinical cardiologists and basic science biochemists will be involved in this effort.